Mechanism of the onset and/or development of hereditary ataxia ; Analysis by ataxic mutant mice

遗传性共济失调的发病和/或发展机制；

基本信息

批准号：
13671139
负责人：
FUKUI Yoshihiro
金额：
$ 2.24万
依托单位：
The University OF Tokushima
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2003
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13671139/
关键词：
rolling mouse Nagoya Ca^<2+> channel ataxia cerebellum inferior olive 6 CRF climbing fiber mossy fiber 苔状線維前庭小脳 unipolar brush cells 蛍光免疫二重染色共焦点レーザー顕微鏡脳幹 in situ hybridization チロシン水酸化酵素ミュータントマウス

项目摘要

Rolling mouse Nagoya (RMN) is an ataxic mutant that carries a mutation in a gene encoding for P/Q-type Ca^<2+> channel α_<1A> subunit. In humans, defects in this gene are responsible for Ca^<2+> channelopathy such as familial hemiplegic migraine and episodic ataxia type-2. Corticotropin-releasing factor (CRF) is widely localized throughout the central nervous system. In the cerebellum, CRF has been found in subsets of climbing and mossy fibers, and plays a role in increasing sensitivity of cerebellar cortical neurons to glutamate, This study aimed to clarify the involvement of CRF-positive cerebellar afferent fibers in the development of ataxic symptoms of RMNIn RMN, CRF immunostaining in some climbing and mossy fibers was much more intense, but the distribution of these fibers remained the same as in non-ataxic littermates (control mice). Double immunostaining for CRF and tyrosine hydroxylase (TH) revealed that TH immunostaining abnormally appeared in some Purkinje cells receiving CRF … More -positive climbing fibers. By semi-quantitative in situ hybridization, the level of CRF mRNA signals increased in some original neurons of the climbing fibers of RMN. Signal levels in the β-nucleus and ventrolateral protrusion of inferior olive (ION) were about two-fold higher in RMN than in the controls. Signal levels in the dorsal nucleus, principal nucleus and subnucleus A of the ION were slightly but significantly higher in RMN than in the controls. In the vestibulocerebellum, the number of CRF-positive mossy fibers was much more in RMN than in the controls. Double immunofluorecence for CRF and calretinin in revealed that some CRF-positive mossy fibers closely opposed to calretinin-positive unipolar brush cells, which play roles in amplifying excitatory inputs from vestibulocerebellar mossy fibersThese results suggest that increased level of CRF in the particular subsets of climbing and mossy fibers alters excitability of cerebellar cortical neurons, involved in the ataxic symptoms of RMN Less

滚动小鼠名古屋（RMN）是一种共同突变体，在编码P/Q-Type Ca^<2+>通道α__<1a_>亚基的基因中携带突变。在人类中，该基因中的缺陷负责CA^<2+>通道病原体，例如家族性偏瘫偏头痛和类型-2偶发性共济失调。皮质激素释放因子（CRF）在整个中枢神经系统中广泛定位。 In the cerebellum, CRF has been found in subsets of climbing and mossy fibers, and plays a role in increasing sensitivity of cerebellar cortical neurons to glutamate, This study aimed to clarify the involvement of CRF-positive cerebellar afferent fibers in the development of ataxic symptoms of RMNIn RMN, CRF immunostaining in some climbing and mossy纤维更加强烈，但是这些纤维的分布与非解剖窝窝（对照小鼠）相同。对CRF和酪氨酸羟化酶（Th）的双重免疫染色显示，某些接收CRF的Purkinje细胞中，TH的免疫染色显着出现……更多阳性攀岩纤维。通过半定量的原位杂交，RMN攀岩纤维的一些原始神经元中CRF mRNA信号的水平增加。 RMN的β-核中的信号水平和下橄榄（离子）的腹侧突出比对照组高约二倍。背侧核，主核和离子亚核A的信号水平略高，但在RMN中明显高于对照组。在前庭纤维中，CRF阳性苔藓纤维的数量在RMN中要比对照组的数量要多得多。 Double immunofluorecence for CRF and calletinin in revealed that some CRF-positive mossy fibers were closely opposed to calletinin-positive unipolar brush cells, which play roles in amplifying excitatory inputs from vestibulocerebellar mossy fibersThese results suggest that increased level of CRF in the particular subsets of climbing and mossy fibers alters excitingness of cerebellar皮质神经元，参与RMN的共同症状较少